WO1998030892A1

WO1998030892A1 - Modular sensor system for the industrial process measurement technique

Info

Publication number: WO1998030892A1
Application number: PCT/IB1998/000044
Authority: WO
Inventors: Ursula Spichiger-Keller; Jürg MÜLLER
Original assignee: Eidgenössische Technische Hochschule Zürich
Priority date: 1997-01-14
Filing date: 1998-01-13
Publication date: 1998-07-16
Also published as: ES2190810T3; DK0953150T3; EP0953150B1; CH692120A5; EP0953150A1; AU7995298A; DE59806935D1; US6409909B1

Abstract

A modular, in particular multidimensional system for the reagent-free, continuous detection of a substance is disclosed. The system is characterised by the presence of at least two measurement modules of preferably different types. The modules are robust and designed for long-time operation. They have an exchangeable or replaceable selective layer structure. The system may also include appropriate modules for amperometry and optical sensors.

Description

Modular sensor system for process measurement technology

Cross-Reference to Related Applications This application claims priority from Swiss Application 64/97, filed January 14, 1997, the disclosure of which is incorporated by reference in its entirety.

Technical field

The present invention relates to process measurement technology, in particular a sensor system for process measurement technology, which enables the continuous and selective acquisition of various measurement parameters.

State of the art

Sensor systems are already known and are described in the prior art.

The best-known systems for continuous on-line measurement technology are the FIA systems (Flow Injection Analysis). These systems consist of a complex fluidics system with pumps and valves. They use traditional analytical methods of determination with reagents and sometimes biosensors or ion-selective electrodes (ISE) at the end of the flow system as detectors.

The known sensor systems are exclusively defined and specified by using either potentiometric or voltammetric (electrochemical measurement of the change in the oxygen partial pressure) or amperometric or optical measurement technology. The company YSI (2700 SELECT) offers a measuring device with biosensors for continuous process measurement technology. The sensor elements are in a miniaturized measuring chamber, in which the examination material is filled in and extracted again. The amperometric or voltammetric systems include the biosensors and miniaturized modified electrodes such as "glassy carbon" or "carbon paste" graphite electrodes [cf. Kalcher, K .; Kauffmann, J.-M .; ang, J .; Svancara I .; Vytras, K; Neuhold, C. ; Yang, Z. Electroanalysis 7/1 (1995) 5-22 (Review)]. Publications were made in particular with regard to arrays (series connection of several sensors that are identical in terms of their functional principle on a geometrically defined sensor surface) using miniaturized sensors, so-called solid-contact electrodes or ISFETs (ion-selective field-effect transistors) [cf. Schindler, JG; Schindler, MM; Herna, K; Reisinger, E. ; Kulmann, U .; Graef, R .; Lange, H. Biomed Tech 36/11 (1991) 271-280, 282-284. (HCA 116: 136186.); van der Schoot, BH; Jeanneret, S. ; van den Berg, A.; de Rooij, NF Sensors and Actuators B 15 / 1-3 (1993) 211-213; Hoffmann,.; Rapp, R.; Ache, HJ; Stolze, D .; Neuhaus, D .; Hofmann, D .; Freywald, KH Micro Total Anal. Syst., Proc. μ-TAS'94 Workshop Ist (1995). in van den Berg, A.; Bergveld, P. (Eds). Dorrecht: Kluwer, Netherlands]. On the one hand, these systems lack the robustness (ruggedness), in particular the layer structure and the reference system, and on the other hand the flexibility to be able to react to new developments. Depending on the manufacturing technology, they are also only for a limited selection or Types of selective layers can be optimized. This limits their application possibilities. Changes to microstructured sensor platforms are hardly worthwhile or only if extremely large quantities can be produced. On the other hand, due to their unsatisfactory robustness and long-term stability, the miniaturized sensors are mainly brought onto the market as "one-way" sensors (i-STAT). This induces the production of waste from precious materials. Continuous measuring systems generally need the possibility of recalibration in order to produce high reliability of the results. However, calibration-free systems have also already been investigated [Rumpf, G .; Spichiger, UE; Bühler, H .; Simon, W .; Anal. Sciences 8 (1992) 553-559)].

The selective determination of certain components of a mixture of the substance is only possible by using so-called selectivity principles. A large number of selectivity principles based on recognition molecules, e.g. selective ligands, or effective principles of selectivity, which are based on distribution equilibria, are known [Fluka catalog "Selectophore®", 1996]. Some of these selectivity principles, e.g. the magnesium, nitrite, heavy metal selective ligands and layers have been significantly further developed [Schaller, U .; Bakker, E .; Spichiger, U.E .; Pretsch, E. Talanta 41/6 (1994) 1001-1005; Spichiger, U.E .; Eugster, R .; Citterio, D .; Li, H .; Schmid, A.; Simon, W. In: S. Golf, D. Dralle, L. Vecchiet (Eds) "Magnesium 1993" London: John Libbey & Co p. , 1993].

Substance-selective ligands are dissolved in the bulk of a layer. This layer or membrane often provides satisfactory selectivity only after careful optimization of the bulk medium, for example the bulk composition. If such a layer is incorporated into pre-existing sensor elements by pouring, gluing, photopolymerization, etc. polymerization processes often have to be taken into account with a considerable loss of selectivity or sensitivity.

The process technology for applying layers and for immobilizing selectivity principles by means of photopolymerization severely limits the possibilities of using selective layers and does not exhaust the potential of the detection components. Despite the extremely large number of known ligands and recognition components, only a few have so far been placed in one layer and tested for analytical applications. So far, only isolated ligands have been used in chemical sensors. The use of chemical sensors in measuring instruments has been a permanent fixture in medical technology for years. Electrolytes are determined in automatic machines for daily routine, but also in "bed-side" analyzers or devices for the doctor's office using ion-selective sensors. The first device to use optical sensors is on the market {OPTI, AVL Biosense Corp., Atlanta). The device works with "disposable cartridges" and offers the parameters pθ2, pC02 and pH (fluorescence emission measurement). Separate

Recently, devices have a combination of biosensors (voltammetric or amperometric determination of the change in the oxygen partial pressure, for example according to 01sons, L. et al., Anal.Chim. Acta 224 (1) (1989) 31 ff) for lactate , Glucose, peroxide, glutamate, creatinine implemented together with ion-selective electrodes. These combinations are based on miniaturized sensors based on solid derivatives or semiconductor elements of the ISFET / ENFET type (ion-selective, enzymatic field-effect transistors), in which the conductivity or. Potential change over the semiconductor element is detected. The company ISTAT has brought such a combination onto the market as "disposable sensors" for single use. These sensors have the disadvantages already described above, i.a. lack of robustness and large amounts of waste.

One company that has been selling an ExacTech® amperometric glucose sensor for self-testing for many years is MediSense Inc. (Waltham, MA), based in Basel; a suitable device for industrial use is the YSI glucose sensor from Yellow Springs (OH, USA). The used in these devices Sensors have several layers, which ultimately lead to the selectivity of the biosensors. Every offered biosensor is based on the same electrode principle, which determines a measurement of the oxygen consumption with the conventional electrochemical oxygen electrode.

Since 1988, more than 1000 publications on glucose biosensors have been published (cf. Gorton, L. Electroanalysis 7/1 (1995) 23-44.) In contrast, optical sensors have hardly been introduced. WPIDS (World Patents Index No) 95-256069 [34] describes the optical measurement of scattered light in living tissues and WPIDS 93-213750 [26] describes the optical measurement of blood hemoglobin content (measuring of blood hemoglobin content).

The aim of the present invention was therefore to provide a measuring system, in particular for continuous process measurement technology, which does not have the disadvantages of known sensor systems and sensors and which is particularly characterized by great flexibility and robustness.

Presentation of the invention

The desired goal was achieved by providing a continuous, modular, especially multi-dimensional, and robust measuring system that is ideally operated without reagents, as well as by providing special modular sensor elements and detection systems suitable for such sensor elements.

For a better understanding of the invention, some basic terms are defined in advance:

- Multi-dimensional (modular), modular, continuous measuring system; Sensor element; Half cell; Measuring module; Reference; Reference module A continuous measuring system based on sensor elements requires that these sensors work reversibly or within the desired reaction time, that is, that their signal resp. continuously adjusts the generated measurement variable to the briefly changing properties of the specimen. The measuring system can enable continuous measurement both in batch and in flow. The term modular means that the individual sensors and sensor groups / types / methods are implemented as sensor elements in individual modules and can be combined as such. The different sensor elements can be implemented, for example, in rod-shaped modules, for example for reactor technology. Such modules are particularly suitable for flow. Characteristic, suitable dimensions of these modules can also be used to combine different measurement methods in the same measurement system. This makes the system multidimensional, since the information about the substance can be obtained on the basis of mutually independent measuring methods. Multi-dimensional (multidimensional) denotes the property of the measuring system that several sensors or sensor elements or measuring methods are combined and thus several substances can be determined in series or in parallel. Two methods, ie two different types of modules, can also provide independent, ie orthogonal information about the same substance and thus increase operational safety (for example an optical and a potentiometric or an optical and an amperometric module). A module can also contain only one half cell or a reference element of a sensor element or more than one sensor or derivation element. In the following - where a specification is necessary - a module that serves the measurement itself, be it a half cell or a complete element is called a measuring module, while the reference element or the reference half cell is referred to as the reference module. - robustness

Robustness is generally understood to mean the low dependence of the generated measurement variable on small changes in the parameters of the measurement system or the low susceptibility to interference of a measurement technology or the measurement system, which can also include long-term stability. The robustness can be further improved by automating the measurement technology and by automated recalibration.

- substance, target substance, analyte; Group of target substances, accompanying substances,

The target substance or analyte (target component and target analyte) is the substance or a group of substances / class of substances that is used to obtain (physico-chemical) information. This information will generally serve to quantify the substance in its medium and provide quantitative information, which is followed by a decision making. The chemical sensor element or a group of sensor elements is in a position between the target substance or. a group of

To differentiate between target substances and accompanying substances and to discriminate between the accompanying substances.

- Selective layer structure; Principle of selectivity

In the layer structure, the selectivity principle or the recognition step and the transduction step (see below) form a successive unit. The layer structure can consist of a single layer or several layers, including auxiliary layers with defined functions. One speaks of a selective layer structure.

- selective detection device; Selectivity principle consisting of: recognition step; Distributional balance; Partition; Recognition component; free of reagents

The detection step leads to the typical selectivity of each individual sensor or sensor module. As a result of the principle of selectivity, the target substance is preferred over accompanying substances. The selectivity principle can be based on distribution equilibria / partition and / or typical chemical interactions between the target substance and at least one recognition component. The layer structure contains the essential components of chemical detection. The selectivity principle is usually reversible or can be regenerated according to the timing of the continuous measuring system. The combination of these steps can be referred to as a selective recognition device.

- transduction step

A transduction step is a step or a sequence of steps that induces or induces. triggered by the selective recognition step or the selectivity principle, which causes the formation of a generally quantifiable measurement variable.

- Measured variable

The formation of the measurand is the result of the recognition step with its typical selectivity principle and the subsequent transduction step. The measurand can already change as a result of the create a change in the distribution equilibrium based on the selectivity principle (potentiometry, IR spectroscopy) or by coupling auxiliary substances (eg indicators) to the detection step.

- information

After being derived and possibly amplified on a data acquisition and processing system, the measurement variable leads to the formation of information about the target substance or a group of target substances. The measured variable often has to be compared with a reference variable in order to obtain greater certainty. The information can consist of qualitative but mostly quantitative information, but also evaluation or Classification criteria included.

The terms defined above are used in the following in the meaning given. The modular system according to the invention for the continuous, reagent-free determination of a substance is characterized in that it has at least two measuring modules of the same or different module types for the simultaneous acquisition of at least two pieces of information, each module containing at least one interchangeable selective layer structure and a discharge device, the Layer structure enables a selective detection step and allows continuous measurement. In a preferred embodiment of the measuring system, different module types are combined, for example at least one ion-selective module and at least one module of another module type, etc. With 3 modules, 1 module can contain a reference system. The reference system differs from the measuring module in that it does not contain a selectivity principle or in that the selectivity principle is not active. The present invention further relates to a method for the continuous determination of a substance, the use of the system and modules and recognition components which are suitable for use in the measurement system. Special embodiments are described in the subclaims.

Reversible and quickly regenerable chemical sensors are characterized by the possibility of continuously measuring a target component, the substance. To obtain continuous information about a wide range of substances, only the FIA (Flow Injection Analysis) is to be mentioned as a comparable measurement technique. In contrast to chemical sensors, the FIA uses traditional chemical reactions using reagents. The process is characterized by a highly developed but cost-intensive fluidics system.

In contrast to existing measuring systems, the measuring system according to the invention is distinguished by maximum flexibility, freedom from reagents and robustness with regard to the nature of the test material and with respect to the continuous long-term measuring technology. Therefore it can also be used for the determination of gases and volatile substances. The advantages according to the invention can be further improved by automation. The flexibility is achieved in that in principle all known sensor types can be implemented; in particular, potentiometric and / or voltammetric measuring techniques can be combined with at least one other measuring technique, for example a perometric and / or optical. The combination of such different measurement techniques enables the provision of the broadest information about one or more target substances. Furthermore, the combination of such different measurement techniques for the measurement of the same target substance gives the greatest possible guarantee for correct measurement results, particularly in the case of low-calibration or -free Systems. The selective layer structure, which is characteristic of each module and in which the recognition and transduction step preferably takes place, forms the heart of the sensor element. The robustness of the sensor element is guaranteed by the optimization of the layer structure, by the reference formation, the automation, by the construction of the module and the modular structure.

An essential feature of the system is therefore that the principle of selectivity, the selective

Layer structure, is interchangeable; it is interchangeable among a variety of available layers and, according to a limited life, interchangeable. The principle of selectivity, the selective layer structure, can be packaged on a carrier and traded in different sizes. Such a carrier can already exist in the lead system (e.g. planar waveguide, planar or rod electrode, optical fiber, resonator, SAW chip). The interchangeable selectivity principle can then be referred to as a chemically active chip. The chemically active chip or chemochip is an essential element of the measuring system. Furthermore, one of the essential features is that not only different sensors but also different types of sensors are connected to one another as independent modules in series or in any other arrangement. The series connection is preferred for flow measurement (optimal throughput of specimen). Parallel connection is preferred for the measurement of test material that has to be conditioned in different ways (pH, ionic strength, temperature etc.).

A module contains all the elements necessary for the selectivity principle, the recognition step, the transduction step, the formation of the measured variable and the derivation. It is due to its robustness several times. can be used continuously over a long period of time. The principle of selectivity, the analyte-selective Layer, due to the special type of implementation, eg for sterile or aseptic measurement technology, can be calibrated from the side where the lead is introduced. This is possible because the conductor element is not necessarily inseparably connected to the selective layer structure.

The individual module works without reagents. The term reagent-free means that no auxiliary substance is used as the reagent that enables the chemical detection reaction in addition to the selectivity principle. The modules according to the invention thus differ greatly from FIA technology and related continuous measurement systems. Buffering, addition of co-substrate or other conditioning agents are not referred to as reagents and are therefore not excluded by the term reagent-free.

A single module can also consist of only one half cell, another can then be the reference system, which is also robust due to its (buffer) capacity and therefore long-term stable. The combination of various independent sensor modules with different functional principles to form a measuring system is known as a multidimensional or multidimensional system. Each module can be independent of the other and make an optimal orthogonal contribution to the final information about the substance (s). The harvest for the user is that he no longer has to selectively select the measuring technology, but only determines which analytical parameters or target substances (target co pounds) he needs information about and which analytical specification (analytical performance) he knows to meet want. He can then leave it up to the provider, for example, to decide which measurement techniques, ie sensor modules, should preferably be combined under these circumstances. The same applies to deciding how many measurement techniques and modules to use are to be combined in order to achieve the specified specifications and the best possible operational reliability.

Experience with different sensor technologies shows that different principles have different properties, which may be more or less suitable, but that no basic technology alone can cover optimal operation for different applications. It was found, for example, that optical measurement technology is characterized by its simplicity and fast response for measuring the dissolved oxygen (the partial pressure in solution in solution) and is therefore suitable for modular sensors and. Sensor systems according to the present invention is particularly suitable. In this regard, optical measurement technology is a good alternative to electrochemical sensors. Optical measurement technology is also possible for measurements of sodium, potassium and calcium, nitrite and chloride activity as well as numerous uncharged target components and substrates such as alcohols, amines, glucose, moisture, lactate, etc. Gases such as NO _x , SO2, NH3 including directly in the specimen.

Specially suitable calibration-free assays are, for example, the luminescence decay time as in Draxler, S .; Lippitsch, M.E .; Klimant, I .; Kraus, H .; Wolfbeis, 0 .; J.Phys.Chem. 99/10 (1995) 3162- 3167 and the symmetrical measuring technique: G.

Hull; U. Spichiger-Keller; H. Buehler and W. Simon; Calibration-Free Measurement of Sodium and Potassium in Undiluted Human Serum with an Electrically Symmetry Measuring System. Anal. Sciences 8: 553-559 (1992). The symmetrical measurement technology, for example according to Haase, AE; Investigation of the interaction between ion-selective liquid membranes and measured material with regard to the continuous detection of cations in the blood. Diss ETH No. 10453 (1993) is suitable for the production of reference materials for the quality assurance of the electrochemical determination of the active molality of ions. Such reference materials lien / quality control samples are currently not available worldwide.

It has now been found that using such a symmetrical measurement technique, respectively. by using symmetrical membranes, which are optimally compatible with the specimen, and a symmetrical arrangement / configuration of the measuring cell, reference materials for determining the molar activity of ions, for example for quality assurance, can be produced. For example, aqueous solutions of lyophilized blood plasma or serum can be used as reference material.

Especially for measurements in pharmaceutical resp. Medical and food sector, it is necessary. useful to sterilize the modules. In this regard, reference can be made to common methods of the prior art, e.g. for sterilization on Haase, A.E .; Investigation of the interaction between ion-selective liquid membranes and material to be measured with regard to the continuous detection of cations in the blood. Diss ETH No. 10453 (1993), pp. 82-83. γ-ray sterilization for packaged membranes is possible. It is also necessary to avoid the introduction of toxic components into the measured sample, the specimen. Toxicity of ISEs is e.g. described in Haase, A.E .; Investigation of the interaction between ion-selective liquid membranes and material to be measured with regard to the continuous detection of cations in the blood. Diss ETH No. 10453 (1993). A perometric systems based on the mediators TTF / TCNQ (tetrathiafulvalene-p-tetracyanoquinone dimethane) are generally considered toxicologically harmless.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows an inventive, three-dimensional system for continuous process measurement technology with a potentiometric, an am- perometric and an optical selective sensor element in longitudinal section.

FIG. 2 shows a section perpendicular to the longitudinal axis of the system from FIG. 1 through a potentiometric element with an exchangeable ion-selective membrane,

FIG. 3 shows a section perpendicular to the longitudinal axis of the system from FIG. 1 through an amperometric module according to the invention with a biosensor element, FIG. 4 shows a section perpendicular to the

Longitudinal axis of the system of Figure 1 by an optical module according to the invention with a fiber-optic element,

FIG. 5 shows a section perpendicular to the longitudinal axis of a system corresponding to FIG. 1 through an optical module according to the invention with a diode element,

Figures 6A and 6B illustrate the reaction path of hypoxanthine analysis, wherein

Figure 6A shows the oxidation step and

Figure 6B the reduction step.

The reference symbols in the figures have the meaning given below:

I: Potentiometric module (half cell), ion-selective sensor element

II: Amperometric module (half cell), biosensor module

III: optical module; Fiber optic module for fluorescence or reflection measurement. 1 carrier of the flow system (e.g. from

Aluminum)

2,3,4 Body of the electrode segments of the flow system (e.g. made of polyethyl methacrylates) denotes 2 segments of the reference electrode, lower

part

3 segment of the measuring electrode, base part 4 body of the measuring electrode, head part

5, 6 screws for the tight fixation of the

Modules

Flow channel for the thermostatted water

8 Selective layer structure

9 test channel

10 thermocouple

11 capillary with internal electrolyte 12 discharge device / discharge element

13 reference electrode / reference module (for potentiomefresh / amperometric half cell)

14 body of the diverter element / diverter 15 screw for a tight connection between the membrane / selective layer structure and the test channel

16 detection diode (on plate)

17 emission diode

Way of carrying out the invention

The individual module I, II, III, 13, which is suitable for use in the system according to the invention, consists of the body of module 3, 4, which consists of e.g. Plastic is made (see Figure 1).

The body comprises an interchangeable, selective layer structure 8 and a discharge device 12, and preferably a channel 9 or a hose for the continuous or stop-flow transport of sample or specimen and for the continuous measurement. The body thus comprises the sensor field, where the selective layer structure or the selective detection device

8 (eg ion-selective membrane; enzyme-active paste, optode membrane, coated waveguide, IR waveguide) on the one hand with the sample on the other hand with the Direction 12 is connected and where the detection step takes place, the transduction step, where the detection step is converted into a measurement variable, which is then derived via the discharge device 12 (e.g. inner electrode, optical fiber, detector diode, amplifier and wire for the discharge of the electrical current) and is optionally compared with a reference quantity.

The module can be produced in the appropriate size, preferably in the centimeter to micrometer scale. The individual module can form an independent chemical sensor element or consist in a half cell (e.g. potentiometry), in which case a second module preferably contains the other half cell. Modules can be connected to each other as required and in any arrangement (e.g. connected in series or in parallel). Different modules differ in the recognition and / or transduction step for which one module is designed and by which one module differs from the other. Modules with the same

The principle of transduction and therefore the same design are combined into module types / module classes.

Module types that differ by different measuring principles and thus provide different, independent dimensions of the information about the substance (but are implemented according to the same basic principle) are, for example:

• potentiometric half cell with ion-selective membrane or combined potentiometric ion-selective electrode element

Selective amperometric biosensor element, e.g. with selective conductive layer / paste

• Element with selective detection step and a coated or uncoated optical planar waveguide as a transduction and / or dissipation element • Element with selective detection step and diverting element for absorption, emission or reflection measurement with coated or uncoated optical fiber • Selective "Surface Acoustic Wave" -

Sensor element

• Conductometric sensor element with the principle of selectivity

• capacitive sensor element combined with a detection step

• optical or electrochemical reference element / half cell.

Modules for potentiometry are already known, but the advantage of being interchangeable

Layer structure not yet recorded. It has now been found that potentiometric, but in particular amperometric and optical modules with interchangeable layer structure can be produced and used for continuous measurement technology and can be superior to firmly fixed layers.

An essential part of every module is the selective layer structure.

This comprises at least one component which effects the selectivity of the sensor element, ie allows the preferred detection of the target substance or a group of target substances compared to accompanying substances. The selectivity can be brought about by molecular recognition of the target substance or by the partition of the substance between the sample / speci en and the sensor element (through a distribution equilibrium). The selective layer structure can contain auxiliary substances which are necessary for the formation of the layer and / or support, catalyze and / or reduce the influence of interference, as well as optionally a further tere component, which is responsible for the transduction step. The layer structure includes the possibility of combining the selective layer with auxiliary layers, which, for example, ensure biocompatibility [cf. Wintermantel, E .; Ha SW. (Eds.); Biocompatible materials and construction methods, Berlin: Springer-Verlag, 1996] and / or enable the separation between gaseous, neutral and charged substances and / or form a diffusion barrier. The layer structure can contain both more or less lipophilic / apolar as well as more or less hydrophilic / polar layers as well as micelles or reverse micelles. Such layer structures for optical sensor elements have already been described in Vaillo, E .; Walde, P .; Spichiger, UE; Analytical Methods and Instrumentation, AMI, 2/3 (1995) 145-153. The washing out of components into the sample / specimen is prevented, for example, by high lipophilicity of the components in the case where there is an aqueous sample / an aqueous specimen [cf. Dinten, 0 .; Spichiger, UE; Chaniotakis, N.; Gehrig, P .; Rusterholz, B .; Morf, WE; Simon, W. Anal. Chem. 63 (1991) 596-603 for optical and potentiometric sensors] or by immobilizing individual components. The selective layer structure is inventively neither with selectivity or sensitivity-reducing processes are still glued in by means of such processes, but rather, if possible, transferred to a system in their "native" form, ie in the form in which it results from the manufacturing process. The sealing then takes place solely via the elasticity of the materials, in particular the layer structure. In all of the systems according to the invention described here, this is possible in that the layer structure is only connected to the sensor module (for example by coating the diverter / the diverter element) or inserted into the module but not changed or processed any further becomes. This ensures the greatest possible selectivity or Sensitivity reached.

The selective layer structure can be on a suitable support e.g. on a planar waveguide, on an optical fiber, on a reflective one

Layer, applied on a diffusion barrier or inlaid in a carrier and also offered as a layer structure and used in a module. Such layers are generally referred to in specialist circles as "disposable layers" or "disposable waveguides with target-analyzed selective layers"). When a sensor element is used up, either only the selective element, the layer structure, but also parts of the module or the entire module can be replaced. The individual module or a set is preferably designed so that it can be thermostatted so that it is quickly ready for measurement when installed.

At least one component of the layer structure has the effect that a target substance or a substance class is recognized by the sensor, in preference to accompanying substances, and leads to the formation of a measurement variable. The selective detection can be induced by a distribution equilibrium of the substance in favor of the layer structure or by a defined chemical interaction, complex formation, reversible chemical reaction, between the target substance and a recognition component or by a typical physical or spectral property.

All natural, synthetic and hybrid molecules can be used as recognition components. Such recognition components are, for example, enzymes, receptors, antibodies and their hybrids or fragments; Carbohydrates, lectins, lipids, peptides, proteins and their hybrids or fragments; synthetic ligands, hydrogen bond formers, inclusion compounds, solubilizates, micelles, reverse micelles, liposomes, associates, complexes, organometallic complexes, reaction products te; Carriers, ionophores, reactants and chromophoric reactants, chromoionophores, redox dyes, electron donors and acceptors, "charge transfer" compounds, pH indicators, components for energy and charge transfer; Macromolecules, organs, organelles, microorganisms.

The detection step can be facilitated by catalysts and other auxiliary substances (plasticizers as solvents, polymers and ions). to be favoured.

Due to the combination of different detection systems, the target substance or substance class covers a very broad spectrum of substances. Examples are: Use of the system according to one of claims 1 to 5 for the determination of inorganic and organic ions, charged, uncharged or neutral molecules, salts, isotopes, radicals, cells or cell components, organisms, microorganisms, viruses, organelles, or receptors in the test material. The at least one transduction step leads to the formation of a measurement variable as a result of a physico-chemical event or via the coupling of a second chemical transduction process. The transduction step can also combine and combine more than one of the principles.

The transduction step is, for example, the formation of an interface potential in the sequence of the detection step / distribution equilibrium. Other examples are: the generation of an electrical current as a result of a redox process, spectral or frequency changes, the changes in resistance or conductivity, the absorption or luminescence intensity, the polarity, the optical strain, the capacitance, or the change the mass, the number of particles or quantum yields as a result of the recognition step, etc. The measurement variable consists in a counting result, in the quantification of the absorption, absorption change in the bank, emissions or frequency, in the change of the current (I), the potential (EMF) or the conductivity (σ), in the change of the mass (m), the temperature (T), the decay time (t) or the service life (tiim), ^etc. - These parameters are converted, if necessary, by calibration and comparison with a reference in, for example, concentration units or in the appropriate language of information.

In the following, some sensors or. Modules described to describe the invention in more detail. These figures and examples are not intended to limit the subject matter of the invention in any way.

Multi-dimensional modular measuring system

Figure 1 shows the arrangement of a measuring system (flow) with four modules I, II, III and 13, a potentiometric I and an amperometric II sensor module each designed as half cells, a module with the reference element 13 (second half cell), and an optical module III . The modules are arranged with the derivative 12 transversely to a carrier 1. They are tightly fixed by screws 5, 6 arranged parallel to the support 1. The flow channel 9 for the sample / specimen of an individual module meets exactly that of the neighboring module and is sealed against leakage by a rubber ring.

The potentiometric module

In the potentiometric module I, the ion-selective layer is placed on a sensor field and is in contact with the sample / specimen via the sample channel 9 open at this point (see FIGS. 1 and 2). In this case, the module is thermostatted with water 7; however, a Peltier element can also be installed or, if desired, the entire system can be thermostatted with air. Base part 3 and head part 4 can, for example, be produced independently of one another and, after the layer structure 8 has been introduced, can be joined / closed using a fastening element, for example screws 15. The head part 4 contains the sensor element with the layer structure 8 and the body of the discharge device 14, respectively. the discharge device / the discharge element 12, here a discharge electrolyte and a discharge electrode.

This head part 4 is preferably designed in such a way that only the placement by sensor elements does not significantly change the plastic construction. In this way, the head and base part can be produced in large numbers and thus cost-effectively. This also ensures the interchangeability of the modules and thus the flexibility of the system.

The amperometric module (Mediated biosensor electrodes)

It has now been shown that an amperometric biosensor module type can be constructed according to the same construction plan as the potentiometric module (cf. FIGS. 1 and 3). The ion-selective layer structure 8 of the potentiometric (ISE) module is replaced by the layer structure 8 of the biosensor. The diverting element 12 here preferably consists of a platinum wire, which resp. In direct contact with the layer structure. the "paste" is there. The "paste" contains the desired enzyme as a recognition component, and preferably TTF / TCNQ (tetrathiafulvalene-p-tetracyanoquinone dimethane) as mediators and a bulk medium, for example silicone oil. Corresponding pastes have already been described [cf. Korell, U .; Spichiger, UE Electroanalysis 6 (1994) 305-315]. The paste can be inserted into the head part 4, for example in the form of a tablet of adapted viscosity or together with a carrier (for example made of polyolefin), placed on the sensor field or introduced connected to the exchangeable lead electrode 12. In a preferred embodiment, the sample channel 9 forms the counterelectrode in zones. For example, it consists of a platinum tube in zones. The reference module 13 remains the same as with the potentio etric module type. It preferably consists of a "free-flow free-diffusion" electrode, as described (non-modular) in Dohner, R .; Wegmann, D .; Morf, WE; Simon, W. Anal. Chem. 58 (1986) 2585-2589. In continuous operation, this electrode has proven to be extremely robust and low in interference.

The optical sensor module

It has also been found that optical sensors can also be used for continuous, robust measurement technology. The structure of a module according to the invention is as follows:

The optical sensor module is in turn designed so that only the sensor elements

(Layer structure 8 and derivation device 12) change in the head part of the module (see FIGS. 1, 4 and 5). A disposable element should preferably be used as the waveguide, on which the layer structure is, for example, grown or at least one selectivity principle is implemented / coupled. The waveguide can simultaneously enable the transduction step and be responsible for the derivation as a derivation device 12. Waveguides can be coated grating couplers, for example, which are applied to the sensor field, the selective layer structure 8, or are inserted / installed in the head part 4. The measurement variable for optical sensors can, for example by measurements of the absorption / absorbance in ATR mode (attenuated reflection) [cf. Spichiger, UE; Freiner, D .; Lerchi, M .; Bakker, E .; Dohner, R.; Simon, W. SPIE Vol 1796 (1992) 371-382], by measuring refractive index changes [cf. Freiner, D .; Kunz, RE; Citterio, D .; Spichiger, UE; Gale, MT Sensors and Actuators B 29 (1995) 277-285], by measuring the optical strain, the phase shift, the reflection or the luminescence decay time or by deriving the luminescence emission.

The light energy can be radiated in from outside the module via an optical fiber or other optical waveguide or the light source can be integrated into the head of the module by the implementation of diodes (emission diode 17, LED). A detector diode 16 can also be integrated in the head of the module (cf. FIG. 5). The discharge device 12 is, for example, an electrical cable.

In all of these module types, the layer structure 8 and the diverter 12 can be separated, i.e. individually exchangeable. This optimizes the versatility of the system and minimizes costs. Due to the similar structure of the modules, they can be optimally combined so that they enable the simultaneous and continuous measurement of various parameters in the sample.

It is also possible to construct the diverting element 12 so that it can be exchanged for the body 14, so that this element can be exchanged without having to also replace a head 14 which may contain expensive electronics. Examples

Recognition components

The principle of selectivity or the recognition step, for example by means of a recognition component, is essential for each module. Potentiometry: Detection components that are especially suitable for potentiometry are selective complexing agents. Some are described in more detail below.

The magnesi selectively complexing agents ETH 3832 and ETH 5506 have proven to be by far the most effective ligands [cf. Spichiger, U.E .; Rumpf, G .; Haase, E .; Simon, W .; Switzerland .Med.Wschr. 121: 1875-1879 (1991); Spichiger U.E., Electroanalysis 5 (1993) 739-745]. However, their optimal selectivity is linked to an optimized composition of the layer or membrane [cf. Spichiger U.E .; Eugster, R.; Citterio, D .; Li, H .; Schmid, A. and Simon, W. (1993), Magnesium activity measurements: facts and enthusiasm, In: Golf, S .; Dralle, D .; Vecchiet, L. (Ed.), Magnesi around 1993, John Libbey & Co Ltd., pages 49-60]. The optimal composition at the moment is as follows:

Ligand ETH 3832 or ETH ^T 5506 1 - 2% by weight plasticizer ETH 8045 approx. 62% by weight

KTpClPB (potassium tetrakis [3,5-bis (trifluoromethyl) phenyljborate) 155 mol% relative to the ligand PVC or hydroxy-PVC approx. 35% by weight.

The ligands are described in Spichiger UE; Eugster, R .; Citterio, D .; Li, H .; Schmid, A. and Simon, W. (1993), Magnesium activity measurements: facts and enthusiasm, In: Golf, S .; Dralle, D .; Vecchiet, L. (Ed.), Magnesi around 1993, John Libbey & Co Ltd., pages 49- 60 and 0 'Doneil, J .; Hongbin, L .; Rusterholz, B .; Pedraz- za, U .; Simon, W .; Anal. Chim. Acta 281 (1993) 129-134, the plasticizers under Eugster, R .; Rosatzin, T .; Rusterholz, B .; Aebersold, B .; Pedrazza, U.; Rüegg, D .; Schmid, A.; Spichiger, UE; Simon, W .; Plasticizers for liquid polymeric membranes of ion-selective chemical sensors, anal. Chim. Acta, 289 (1994) 1-13. Instead of ETH 3832, other lipophilic, higher alkylated derivatives can be used, such as the dodecyl derivative ETH 5405 (Spichiger UE, El ectroanalysis, 5 (1993) 739-745). Instead of ETH 8045 as a plasticizer, ETH 5373, ETH 220 and others can be used.

To produce the selective layer, the components are dissolved in a volatile organic solvent (for example THF, chloroform, methylene chloride, cyclohexanone and mixtures). The selective layer is according to Oesch, U.; Brzozka, Z .; Xu, A.; Rusterholz, B .; Suter, G .; Pharm, HV, Welti, DH; Ammann, D .; Pretsch, E .; Simon, W .; Anal.Chem. 58 (1986) 2285. To increase the biocompatibility of the surface, the layer / membrane can be coated, for example, with a polyurethane preparation dissolved in THF. To do this, the membrane is left to dry on a glass plate. The glass plate, for example with a diameter of 1.8 cm, is fixed on a disk rotating at 600-1000 rpm. Now 0.5-1.0 ml of a solution with 0.3-3.0% by weight of polyurethane (e.g. Tekoflex EG-80A, EG-85A (Thermedics, Woburn)) is sprayed on with a syringe and then left to dry. In this way, a layer structure with advantageous properties is created. The advantage of this treatment is that a surface that is robust against adsorption from the biological sample is created without significantly changing the properties of the selective layer or its response time. Any change in the composition can lead to a partial loss of selectivity and sensitivity. A synthesis for the ligand ETH ^T 5506 is in O'Donnell, J .; Hongbin, L .; Rusterholz, B .; Pedrazza, U .; Simon, W .. Anal. Chim. Acta 281 (1993) 129-134. This includes numerous intermediate products which have to be cleaned chromatographically. The synthesis was therefore simplified in the following steps:

Deprotection of the 1, 3, 5-tris (aminopentyl) benzene protected with a phthaloyl protective group by reduction of the phthalide to the triamidetriol (NaBH4, i-PrOH / H2O 17/3; 12h RT) with 92% yield and pyrolysis of the tria - midtriols (170-200 ° C, 4 atm in the Kugelrohr) with distillation of the phthalide and subsequent distillation of the triamine (200 ° C, high vacuum in the Kugelrohr) in the same step with 95% yield.

The synthesis of the 1-adamantyl-methyl-malonmonoamide building block activated as 4-nitrophenyl ester was also made more efficient. The synthesis of Adamantyla- ins from N-Adamantylmethyltrifluoroacetamid provides poor and non-reproducible yields of the sec. A ins. These problems could be solved by performing the hydrolysis of the trifluoroacetamide with KOH / 18-crown-6 in THF. The much cheaper adamantyl hydrochloride was used as the starting product and this was methylated with methyl iodide. The methylated adamantylamine was continuously refluxed with the malondimethyl ester to give the adamantyl-methyl-malondiamide. The product precipitates from the mother liquor and can be filtered off (80% yield). Unreacted adamantyl methylamine can easily be isolated again. The building block 1-adamantyl-methyl-malonmonoamide activated as 4-nitrophenyl ester is obtained in 40% yield over both stages.

Ligands for the determination of heavy metals, especially lead:

Lipophilic 19-di- and trithiacrown-6 isologues as PbOH ⁺ -selective ligands were developed for the determination of lead in drinking water, groundwater and waste water. Previously developed ligands showed copper selectivity, which before the analysis of water samples was insufficient and the selective analysis of lead ions did not allow [cf. Lerchi, M .; Bakker, E .; Rusterholz, B .; Simon, W. Anal. Chem. 64 (1992) 1534 ff .; CTI project No. 2692.1; EUREKA project "ASREM" EU 1013]. Ligands 18, 18-bis (dodecyloxymethyl) -1,4, 13, 16-tetraoxa-7, 10-dithiacyclononecane (5) and 18, 18-bis (dodecyloxymethyl) -1, 7, 10 , 16-tetraoxa-4, 13-dithiacyclononadecane (7) were synthesized and into classic ion-selective PVC membranes with ethyl hexyl sebacate (DOS) or dibutyl sebacate (DBS) as plasticizers and 30 mol% potassium tetrakis [3, 5- bis (trifluoromethyl) phenyl] borate. The selectivity patterns of the two ligands were determined potentiometrically using the IUPAC separate solution method. They are characterized by a discrimination of copper ions by a factor of 10 ^~ 5 ^« 8 and by a discrimination of alkali ions by a factor of <10 ^-3 (molar concentration units). The significant influence of the plasticizer or the medium, the environment, can also be observed here. Preferred plasticizers, respectively. Media are ETH 8045, ETH 220 [described in Eugster, R .; Rosatzin, T .; loc. p. 26, line 27], bis (2-ethylhexyl) adipate (Fluka Chemie AG, Selectophore).

Synthesis and use of chromogenic ligands for carbonate, moisture and primary alcohols

Various trifluoroacetylaniline derivatives have been described by Keller-Lehmann, B. ; Diss ETH No. 9255, trifluoroacetophenone derivatives as carbonate-selective ionophores in PVC liquid membrane electrodes (1990) and proposed as reactive recognition components for the selective determination of carbonate, moisture and primary alcohols. The recognition reaction consists in the formation of a hemiacetal and is reversible. The ligands have been successfully used in optode and electrode membranes [see. Wild, R .; Citterio, D .; Spichiger, J .; Talking UEJ Biotech. 50 (1996) 37-46]. For the detection in optical sensors, the decrease in the absorbance of the aromatic trifluoroacetyl group as a result of the hemiacetal formation is observed at a wavelength of approximately 305 nm. However, this wavelength is poorly suited for the construction of mobile, inexpensive sensor elements. A group of chromogenic reactants was therefore developed which absorb in the visible region of the spectrum and nevertheless retain the selectivity for the substances mentioned. These are N, N-disubstituted-aminophenyl-4 '-trifluoroacetyl-azobenzenes, N, N-disubstituted-aminonaphthalene-4' - trifluoroacetyl-azobenzenes, 4-trifluoroacetyl-4 '- (N, N-disubstituted-amino) stilbene and disubstituted -p-amino-trifluoroacetylstilbenes, such as, -dioctylamino-phenyl-4 '-trifluoroacetyl-azobenzen, N, N-dioctylamino-naphtalin-4' -trifluoroacetyl-azobenzen, 4-trifluoroacetyl-4 '- (di- N-octylamino) stilbene and p-dialkylamino-trifluoroacetylstilbene. These are prepared according to schemes 1 to 3. The synthesis of the stilbene derivatives was carried out from l-iodo-4-dialkylamino-benzene and l-bromo-4-ethenylbenzene with subsequent acetylation with trifluoroacetyl methyl ester. The substitutes are long-chain and lipophilic. They differ in the electron-inducing effect. Usually your lipophilicity should be at least 3 according to Hansch.

The chromophoric reactants can be covalently bound, for example, to acrylate and methacrylate and immobilized in polymer membranes. Remarks

C ₁ 2H25OH sulfuric acid / 120 ° C

₊ 2 C ₁₂ H _2S Br potassium carbonate / DMF

^~ _N H ₊ Rhodamine B-S0 ₂ C1 or _C ar _b ocyanin-COOH / DCC

Scheme 1

H_N fluorophore

Scheme 2

BuLi CF3COOCH3

Scheme 3 Production of optical selective layers for nitrite, NO _y and chloride determination

Based on known nitrite, NO _χ - and chloride-selective ligands (Nitritionophore I, Fluka Chemie AG, Buchs, Switzerland; chloride-selective ligand ETH 9033 [see Rothmaier, M .; mercury-organic compounds as neutral anion carriers in ion-selective PVC - Liquid membranes, Diss. ETH No. 10812, 1994], layers / membranes for optical sensor elements were produced by using an H ⁺ -selective chromoionophore

(Chromoionophore I, II and VI for nitrite; Chromoionophore III for chloride, Fluka Chemie AG, Buchs, Switzerland) with the nitrite- or chloride-selective ligand and, where necessary for charge compensation, together with anionic or cationic lipophilic excipients dissolved in a DOS plasticized PVC layer. The change in absorbance as a result of the co-extraction of the anion together with H ⁺ from the buffered sample solution is determined photometrically and follows the change in the concentration of the anion. For Ni tri t the measuring range is between

0.24 to 5000 mg kg ^~ l, chloride is discriminated with a selectivity factor of 10 ^{~ 2} - ⁹ (molar units). The measuring range and, depending on the measuring range, also the response speed change with the chro- moionophor used; the chromoionophores show different ones

Stability. The implementation of several optode layers for the determination of nitrite or a nitrite-selective optode and electrode in a system can be desirable depending on the question. The nitrite-selective membrane with Chromoionophore VI as an indicator shows a luminescence emission in the visible range of the spectrum and can therefore also be used as a luminescence-active layer.

The above-mentioned ligands have preferred fields of application, but they can generally be used in optical, potentiometric and any other systems as a selectivity principle, if appropriate in combination with other layers, if necessary also for the determination of gases and volatile substances.

Oxygen determination with optical sensors

A new selection system was developed especially for oxygen determination with optical sensors. Ru (II) complexes with organic ligands, especially Ru (II) - (4, 7-diphenyl-l, 10-phenantroline) 3 complexes have been introduced in the past few years for the determination of the oxygen partial pressure in solution. The Ru (II) complex serves simultaneously as a recognition and transduction component. This takes advantage of the fact that the luminescence emission of the complexes is quenched by 02, i.e. is suppressed. The excitation takes place at 470 nm, the emission maximum is at 607-624 nm depending on the environment / bulk of the layer. The known Ru (II) complexes, despite their association with organic ligands, are very hydrophilic and can therefore hardly be dissolved in an apolar layer. This was only possible by introducing lipophilic groups on the phenyl radical, for example by alkylating the phenyl radical in the 'position. In particular, propyl to dodecyl, particularly preferably propyl to octyl, very particularly preferably propyl to heptyl derivatives are suitable indicators of dissolved oxygen in apolar membrane surroundings. Washing out can be further slowed down by ion pair formation with lipophilic anions or immobilization. Such complexes can be produced in 3 steps according to Scheme 4 and the subsequent cleaning process. 4-Heptyl-ß-chloropropiophenone [according to Case, F., Strohm, P.F., J. Org. Chem. 27 (1962) 1641 ff.] Was produced from 1-phenylheptane and 3-

Chloropropionic acid chloride, the preparation of 4,7-bis (4'-heptylphenyl) -1, 10-phenanthroline [according to Lund, GK, Holt, SL, J. Chem. Eng. Data, 26 (1981) 277 ff.] From 1,2-phenylenediamine and 4-heptyl-ß-chloropropiophenone, and the preparation of the ruthenium (II) complex, Ru (II) [- 4,7- bis (4 ' -heptylphenyl) -1, 10-phenanthroline] 3 [according to Wolfbeis, OS, et al., Anal. Chem. 60 (1988) 2028 ff.] From 4,7- bis (4'-heptylphenyl) -1, 10-phenanthroline and RUCI3.

Scheme 4 The cleaning was carried out with hexane / water, acetone / water and activated carbon, recrystallization from acetone / water, column chromatography with dichloromethane / acetone or chloroform.

Analog synthesis for the propyl or butyl derivative is based on 4-propyl-ß-chlorpropiophenon resp. 4-Butyl-ß-chlorpropiophenon performed.

The excitation in modules according to the invention is preferably carried out via a waveguide or a diode in the head part of the sensor module. The luminescence emission is derived in the same way. The measurement variable or the measurement signal is formed by changing the emission intensity at 607 to 624 nm. This measured variable is compared with the signal of a solution with a known 02 ~ partial pressure, which leads to information about the target substance.

The lifetime of the luminescence emission in plasticized polymers was also examined. This showed good results. The measurement of the decay time is particularly suitable for the implementation of calibration-free systems. Complexes of the ligands mentioned with lanthanides (e.g. Eu, La) lead to further attractive compounds with an extended lifespan for measuring the luminescence decay time.

The use of Ru (II) complexes in the organic phase of reverse micelle systems [cf. Vaillo et al, AMI 2/3 (1995) 145-153] leads to simple and direct indicator layers for the determination of the activity of oxidases (e.g. for lactate, glutamate, glucose oxidase, hypoxanthine, peroxidase) e.g. about oxygen consumption.

In contrast to older selectivity principles, which consist of 2 layers, which were produced according to the disadvantageous state of the art processes described above, the single-layer system is more efficient and therefore more robust against variable 02 pressure. Amperometric biosensors

Part of the selective layer structure of an amperometric biosensor is e.g. a paste which contains an organic mediator as an electron transfer catalyst and according to Korell, U .; Spichiger, U.E. Electroanalysis 6 (1994) 305-315; Korell, U .; Spichiger, U.E. Anal. Chem. 66 (1994) 510-515 can be produced. The redox-active enzyme is introduced into the "paste" and shows an optimal lifespan in this environment. The bulk of the "paste" serves as a reservoir from which active enzyme can be supplied. The "paste" can be introduced into the recess provided for this purpose in the head part of the sensor module (see FIGS. 1 and 3). The surface forms the sensor field where the sample and the selective layer structure are in contact with each other. The paste is preferably highly viscous to elastic, so that it is present directly as a tablet, or it is brought into exchangeable tablet form by means of a carrier.

Glucose determination

A paste containing 20% by weight glucose oxidase (GOD EC 1.1.3.4) in silicone oil / TTF / TCNQ could be operated continuously for 2.5 months (standard parameters: T 25 ° C; working voltage U = +200 to - 200 mV; buffer: 50 mM I idazole / 50 mM NaCl, pH 7.0; flow rate (delivery rate of the peristaltic pump: 0.025 ml / min.) The dynamic measuring range of such a module in the continuous system according to the invention proved to be well suited in the concentration range from 1 to 100 mM (U = - 100mV compared to SCE), with the rotating stick electrode the detection limit is 1 μM (200mV, 25Hz) The paste can also be printed on a carrier material (preferably the electrode material) for mass production and piece by piece as a selective layer structure be used for the assignment of the sensor field. Instead of silicone oil, other bulk materials (see potentiometric ion-selective membranes) can be used. To increase the viscosity and mechanical robustness, an auxiliary, for example a polymer such as PVC, is introduced into the silicone oil.

Using a phosphate-selective sensor, it could be shown that it is also possible to produce a bienzymatic layer in which two enzymes are introduced into the same layer [cf. Müller, JP; Development of a phosphate-sensitive bienzymatic-amperometric biosensor. Diploma thesis ETHZ, 1994]. The phosphate-selective sensor element contains 1 part of TTF / TCNQ (tetrathiafulvalene-p-tetracyanoquinodimethane) manufactured according to Ferraris et al. [J. At the. Chem. Soc. 95 (1973) 948] in 1.6 parts of silicone oil. With this finely ground paste, for example, 3.18% by weight xanthine oxidase (EC 1.1.3.2) and 4.35% by weight nucleoside phosphorylase (EC 2.4.2.1.) Correspond to 7.53% by weight total lyophilizate content mixed. The paste is inserted into the recess (sensor field) provided for this purpose, a modular stick electrode and this is checked in the arrangement of a rotating disk electrode. The paste is stored at -30 ° C. Before the electrode is calibrated and tested, it is conditioned for 16 h in a pH 7.0 buffer solution containing 50 mmol L ^~ imidazole, 50 mmol L ^~ l sodium chloride and 1.2 mmol L ^~ l inosine. For the functional test, an increment of phosphate solution is added to this buffer solution every 2 minutes, which leads to a concentration increase of 1.0 μmol L ^~ l or 5 μmol L ^-1 phosphate. The change in anode current is measured at a rotation frequency of 25.0 ± 0.05 Hz. The change in concentration could be measured within <15s with an applied voltage of -50.010.2 mV. All three sensor elements presented can equally be constructed as rod-shaped module types and, for example, combined in a probe and introduced into a reactor or connected in-line to the reactor. Each Sy stem ^¬ can be several modules include a different type of one type in combination with modules. The several modules of the same type can differ, for example, by different recognition components. The processing of the signals emerging from the individual modules, respectively. The measurement result is output using known methods. For example, a derivation device can be used to derive at least one measurement variable from a measurement module or a reference variable from the reference module to a device for processing the measurement variables, such that the measurement variable can be used for process control.

The information about the substance is obtained, for example as amount, concentration or. Change in concentration, as counting result, time, activity or active molality.

The system is suitable for the determination of inorganic and organic ions, charged, uncharged or neutral molecules, salts, isotopes, radicals, cells or cell components, organisms, microorganisms, viruses, organelles, or receptors and can be used in medical diagnostics and treatment, in the Dialysis and hemodialysis, in clinical analysis, in environmental technology, construction technology, clean room technology, waste water,

Groundwater and drinking water control, in food technology and production, in agricultural technology, in particular in horssol culture technology, in food technology, in biotechnology and chemical process technology, in pharmaceutical research and production, in drug technology and drug control, as well as in textile technology and in detergent and cleaning and surfactant technology.

The selective layer structures can be in various thicknesses. Due to the interchangeability, they can easily be optimized for special applications. The seal between layer structure and Test channel is usually done only through seals, for example made of plastic, and pressing the layer structure by means of the head part, respectively. Discharge element on this seal. The use of selective layer structures means that it is possible to work without reagents. In many cases it will be necessary to dilute and buffer the specimen.

Claims

claims

1. Modular system for the continuous reagent-free determination of at least one substance, characterized in that it has at least two measurement modules

(I, II, III) of the same or different module types for the simultaneous acquisition of at least two pieces of information in the flow, each module containing at least one interchangeable selective layer structure (8) and a discharge device (12), the layer structure (8) having a selective detection step enables and allows a continuous measurement

2. Modular system according to claim 1, characterized in that it is multidimensional, i.e.

Measuring modules (I, II, III) comprises at least two module types.

3. Modular system according to claim 1 or 2, characterized in that the measuring modules are selected from the group comprising potentiometric, voltammetric, amperometric and optical modules.

4. Modular system according to one of claims 1 to 3, characterized in that a measuring module is designed as a chemically selective half-cell and another module as a reference cell (13).

5. Modular system according to one of claims 1 to 4, characterized in that the module contains a channel (9) for the flow of the sample, such that the interior of the sample channel (9) with the selective layer structure (8) of the respective module is in direct contact.

6. A method for the continuous determination of at least one substance using a modular system according to one of claims 1 to 5, characterized in that at least one measurement variable is determined by means of at least two measurement modules of the same or different module types, a selective one Layer structure for each module enables a selective recognition step that the recognition step is connected to at least one transduction step that leads to the formation of a measurement variable, that the measurement variable is derived via at least one derivation device, and that the derivation of the measurement variable leads to at least some of the information about the substance .

7. The method according to claim 6, characterized in that at least one derivation device derives at least one measurement variable from a measurement module or a reference variable from the reference module to a device for processing the measurement variables, such that the resulting information can be used for process control .

8. Use of the system according to one of claims 1 to 5 for the determination of inorganic and organic ions, charged, uncharged or neutral molecules, salts, isotopes, radicals, cells or cell components, organisms, microorganisms, viruses, organelles, or receptors.

9. Use according to claim 8 in medical diagnosis and treatment, in dialysis and hemodialysis, and in clinical analysis.

10. Use according to claim 8 in environmental technology, construction technology, clean room technology, waste water,

Groundwater and drinking water control, in textile technology and in detergent and cleaning and surfactant technology.

11. Use according to claim 8 in food technology and production, in agricultural technology, in particular in horssol culture technology, in food technology, in biotechnology and chemical process technology, in pharmaceutical research and production , drug technology and drug control.

12. Module, characterized in that there is an interchangeable selective layer structure (8), a Diverter device (12) and a body of the diverter element (14).

13. Module according to claim 12, characterized in that it has a layer structure (8) present separately from the diverter (12) and that the diverter (12) can also be replaced together with or separately from its body (14).

14. Module according to claim 12 or 13, characterized in that it has a flow channel (9) and that the layer structure (8) is tightly connected to this flow channel (9) for the sample.

15. Module according to one of claims 12 to 14, characterized in that it has a sample channel (9) which consists at least in zones of the counterelectrode.

16. Module according to one of claims 12 to 14, characterized in that it is an optical module.

17. Module according to claim 16, characterized in that the selective layer structure (8) at least one ligand selected from the group consisting of N, N-disubstituted aminophenyl-4 '-trifluoroacetyl-azobenzenes, N, N-disubstituted-aminonaphthalene Contains 4 '- trifluoroacetyl-azobenzenes, 4-trifluoroacetyl-4' - (N, N-disubstituted-amino) stilbenes and disubstituted p-amino-trifluoroacetylstilbenes.

18. Module according to claim 16 or 17, characterized in that the selective layer structure contains at least one complex of a 4, 7-diphenyl-l, 10-phenanthroline with ruthenium or lanthanides which is lipophilically substituted on the phenyl radical, especially in the 4 'position with an alkyl radical, preferably a propyl to dodecyl, in particular a propyl to heptyl radical.

19. Use of symmetrical membranes and a symmetrical arrangement / configuration of the measurement Cell for calibration-free measurements in systems according to one of claims 1 to 5.

20. Use of symmetrical membranes and a symmetrical arrangement / configuration of the measuring cell for the production of reference materials for the determination of the molar activity of ions for quality assurance, in particular in systems according to one of claims 1 to 5.

21. N, N-disubstituted-aminophenyl-4 '-trifluoroacetyl-azobenzenes, N, N-disubstituted-aminonaphthalene-4' -trifluoroacetyl-azobenzenes, 4-trifluoroacetyl-4 '- (N, N-disubstituted- amino) stilbenes and disubstituted-p-amino-trifluoroacetylstilbenes, the substituents being lipophilic, in particular for use as chromogenic ligands in modules according to one of Claims 1 to 5 and 12 to 18.

22. Complex of a 4, 7-diphenyl-l, 10-phenanthroline substituted lipophilically on the phenyl radical with ruthenium or lanthanides, in particular for optical oxygen determination in measuring systems or. Modules according to one of claims 1 to 5 and 12 to 18.

23. Use of a module according to one of claims 12 to 15, which has an enzyme and mediator-containing paste, for the amperometric determination of phosphate.